Current methods to isolate clusters of DNA fragments linked to a given marker are slow and cumbersome. Methods for in situ hybridization of unique copy gene sequences to human chromosomes are also difficult and at the limit of consistent reliability. In the present application we propose to develop a series of steps that provide a more rapid approach for localization of given unique DNA fragments by in situ hybridization and also for chromosome walking procedures for DNA spanning regions of the chromosome larger than may be propagated as an intact DNA piece in currently available vectors. We propose to apply these procedures to isolate a set of random DNA fragments that are evenly dispersed along the entirety of the human genome and to identify polymorphic fragments within this set so as to develop a universal set of probes for studying linkage of diseases of unknown etiology.